Diabetes is a serious medical condition characterized by the body's inability or deficiency to metabolize glucose. This disease affects almost 250 million people worldwide and is the 4th leading cause of death globally. The number of diabetes patients is expected to increase to at least 300 million in 2025. There are two major types of diabetes mellitus: Type 1 diabetes, caused by insufficient secretion of insulin due to the damage of pancreatic beta cells, which requires frequent administration of exogenous insulin to sustain life; and Type 2 diabetes, often caused by inadequate endogenous insulin to control glucose levels, which is currently managed through dietary modifications, exercise, medication, or through insulin injections in about 20% of the cases. In both types of diabetes, hypoglycemia frequently results from the use of insulin, owing to a very poor approximation of normal physiological insulin secretion that is tightly modulated by glucose levels. In order to maintain blood glucose levels within the normal range, diabetic patients have to administer insulin periodically prior to meals or when it is needed as indicated by self-examination of blood glucose levels. This process is painful, inaccurate, inconvenient, and cannot monitor and deliver necessary insulin at night during sleep. Therefore, research has been conducted actively in past decades to explore better ways of monitoring glucose concentration and delivering insulin continuously and automatically. Unfortunately, development of glucose-responsive insulin delivery systems has still been unsatisfactory, though a few glucose sensors have been or are being developed. In addition, linking the sensor with the insulin pump has been attempted.
Different approaches to insulin delivery have been investigated including delivery of insulin via oral, nasal, or pulmonary routes and transplantation of islet cells. Except for the latter approach, other treatment options cannot provide automatic supply of insulin when needed. Transplantation of pancreatic islet cell into patients was conducted in multicenter clinical trials of Edmonton Protocol (Canada) and showed great promise of normalizing a patient's pancreatic functions. However, because of chronic use of immunosuppressive drugs, limited sources of the cells (only sufficient islets from donors to treat 0.1% of the true need in type 1 diabetes), and the high cost of the treatment ($140K per patient), renders this approach unavailable to the majority of patients. Moreover, to date, long-term function of the transplanted islets has been difficult to accomplish with only 10% of patients maintaining insulin independence 5 years after transplantation. Even for those patients receiving islet cell transplant, interim insulin treatment is necessary to preserve the function of the islet cells at the outset.
Animals, just like humans, can acquire Type 1 or Type 2 diabetes. Canine diabetes is an endocrine disorder which is seen in pets such as cats and dogs and in big animals like horses. Diabetes in animals requires daily management and, in most cases, treatment by owners. In this case, the burden and difficulty of administering treatment and the costs associated with treatment rests on the pet/animal owners. Type I diabetes in animals occurs when there is a lack of insulin production and secretion by the pancreas. This form is identified in approximately 50 to 70% of cats diagnosed with diabetes mellitus, and requires insulin injections to control the disease. Most cats will require one or two daily injections of insulin to control blood glucose. Diabetic dogs almost always (99%) have Type I diabetes and also require one or two daily injections of insulin. The injections are given under the skin using a small needle. Dogs tend to get diabetes early in life. For instance, juvenile-onset diabetes (Type 1) may occur in dogs at less than 1 year of age. Although cats tend to get diabetes later in life, e.g. middle-aged to older, it may also occur in cats younger than 1 year of age.
Type II diabetes occurs when enough insulin is produced but something interferes with its ability to be utilized by the body. This form is identified in approximately 30% of cats with diabetes mellitus. In order to maintain blood glucose levels within the normal range, diabetic animals need to have insulin administered periodically prior to meals or when it is needed as indicated by glucose level examination. As animals cannot do this for themselves, owners have to make sure that their animals are getting the proper treatments at very specific times. The process is painful and uncomfortable for the animals, can be inaccurate and inconvenient, and is clearly a burden on a pet owner.
Numerous groups have attempted to develop closed-loop insulin delivery systems (SRIDS). The principle of SRIDS is to integrate a sensing element and a responsive release mechanism into one system. In addition to the biological approach, i.e., islet cell transplantation, electromechanical and physiochemical approaches have been investigated. In the electromechanical approach, an insulin pump infuses insulin controlled by a computer that receives signals from a glucose sensor. However, to date, no integrated closed-loop insulin pump system is available for human use. Currently available insulin pumps deliver insulin continuously and subcutaneously or intraperitoneally in the case of the external pumps. In 2006 a sensor-augmented pump, the Mini-Med Paradigm® REAL-Time System (Medtronic Diabetes, California) received FDA approval. This system consists of a CGMS Guardian RT glucose monitor and an insulin pump. Although this system can offer better control of blood glucose levels than periodic injections, it is not a closed-loop system. It provides real-time information about carbohydrate count and historical data based on which pump settings can be adjusted by users thus achieving better control of glucose levels. Integrated systems are also being investigated using microdialysis, subcutaneous or intravenous sensors, together with implanted pump or external pump.
While significant progress has been made to close the loop between glucose sensor and insulin delivery pump, this electromechanical approach is not without problems. For example, insulin pumps were recalled due to patient injuries and even deaths associated with use of the pumps. Transmission of blood sugar signals to the pump via radio frequency may interfere with cell phones or radio traffic giving problems inside airplanes. Moreover, the users still need to conduct finger pricking measurements for calibrating the sensors every 24 or 48 hours.
Physicochemical approaches to the development of SRIDS utilize physical interactions or chemical reactions that trigger changes in polymer properties allowing more or less insulin to be delivered. Similar to the principal mechanism of most glucose sensors, glucose oxidation by glucose oxidase (GOx) is used to generate pH or hydrogen peroxide signals. Polymers containing amino groups swell at lower pH in response to higher glucose levels allowing more insulin to be released either by creating larger pores or by pushing insulin solution out. The disadvantages of such an approach include slow response of the bulk hydrogels, weak mechanical strength, and possible binding of negatively charged insulin with positively charged polymers hindering insulin release. Carboxyl group-containing polymers, e.g. poly(acrylic acid), were grafted onto a porous membrane/filter and used to regulate insulin release by glucose oxidation. This method offered a faster response and higher mechanical strength than the bulk hydrogel, however, it resulted in very low enzyme immobilization and difficult control of surface grafting. Redox polymers have been applied with glucose oxidation, however, hydrogen peroxide is produced. The polymers changed from reduced form (hydrophobic) to oxidized form (hydrophilic), thus increasing the permeability of insulin through the polymer. This method suffers a very small change (<1.5-fold increase) in insulin permeability as glucose concentration was raised from zero to 5,000 mg/dL, which is unrealistically high as compared to 200-400 mg/dL, hyperglycemia levels in the body.
Competitive binding of glucose with sugar ligands and competitive binding of glucose with polymers are other physicochemical approaches. Glycosylated insulin forms a complex with lectin. As free glucose diffuses into the complex, the glycosylated insulin is replaced and released out. This binding mechanism is non-specific because other endogenous sugars can also bind with lectin, resulting in false signals. Competitive binding of free glucose with polymers is also used to induce polymer swelling or dissolving, thus increasing insulin release. This method is also problematic because other diols or sugars in the body can bind to boronic acid and concanavalin-A.
In view of the foregoing, it is evident that there is a need to develop alternative ways of treating diabetes, in both humans and animals, that allow for effective and accurate treatment.